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The molecular binding was stabilized through four hydrogen bonds with Glu166 and Thr190 as well as hydrophobic interactions via eight residues. The SARS-CoV-2 Mpro shows identities of 96.08% and 50.65% to that of SARS-CoV Mpro and MERS-CoV Mpro respectively at the sequence level. At the structural level, the root mean square deviation (RMSD) between SARS-CoV-2 Mpro and SARS-CoV Mpro was found to be 0.517 Å and 0.817 Å between SARS-CoV-2 Mpro and MERS-CoV Mpro. Bonducellpin D exhibited broad-spectrum inhibition potential against SARS-CoV Mpro and MERS-CoV Mpro and therefore is a promising drug candidate, which needs further validations through in vitro and in vivo studies.Human coronaviruses, especially COVID-19, is an emerging pandemic infectious disease with high morbidity and mortality. Coronaviruses are associated with comorbidities, along with the symptoms of it. SARS-CoV-2 is one of the highly pathogenic coronaviruses that causes a high death rate compared to the SARS-CoV and MERS. In this review, we focused on the mechanism of coronavirus with comorbidities and impairment in multi-organ function. The main dysfunction upon coronavirus infection is damage to alveolar and acute respiratory failure. It is associated with the other organ damage such as cardiovascular risk via an increased level of hypertension through ACE2, gastrointestinal dysfunction, chronic kidney disease, diabetes mellitus, liver dysfunction, lung injury, CNS risk, ocular risks such as chemosis, conjunctivitis, and conjunctival hyperemia, cancer risk, venous thromboembolism, tuberculosis, aging, and cardiovascular dysfunction and reproductive risk. Along with this, we have discussed the immunopathology and coronaviruses at a molecular level and therapeutic approaches for the coronavirus infection. The comorbidities and multi-organ failure of COVID-19 have been explained at a molecular level along with the base of the SARS-CoV and MERS-CoV. This review would help us to understand the comorbidities associated with the coronaviruses with multi-organ damage.Aims N-Acetylcysteine (NAC) is an effective antidote for the treatment of acetaminophen (APAP) poisoning; however, due to its low stability and bioavailability, repeated dosing of NAC is needed. This study investigated the therapeutic efficacy of NAC by niosomal carriers. Materials and methods Niosomes were synthesized using surface active agents film hydration method and their physicochemical properties were characterized. In the in vivo study, in addition to control group, male rats were divided in different groups and challenged with an oral dose of APAP (2000 mg/kg); 4 h later, rats were administered normal saline, empty niosome (NIO), NAC (25 mg/kg) and NAC-loaded niosome (NAC-NIO) respectively, and sacrificed 48 h post-APAP overdose. Key findings The particle size and zeta potential of NAC-NIO were 242.3 ± 18.5 nm and -23.9 ± 1.6 mV. The loading and encapsulation efficiency of niosomes were 1.22% ± 0.02% and 26.76% ± 6.02%. APAP administration leads to hepatic damage as evidenced by increases in serum hepatic enzyme levels and tissue levels of nitric oxide and lipid peroxidation as well as decreases in hepatic levels of reduced glutathione, catalase, superoxide dismutase, and glutathione peroxidase. Treatment of rats with NIO-NAC was remarkably more effective than NAC in improving biochemical changes such as serum hepatic aminotransferases. These findings were correlated well to the histopathological experiments. Significance Our results suggest that NAC when delivered as a niosomal structure, is potentially more effective than NAC standard, in improving APAP-induced hepatotoxicity.MicroRNAs have been demonstrated to play critical role in the development of non-small cell lung cancer (NSCLC) and hypoxia is a common hallmark of NSCLC. MiRNA-130a-3p (miR-130a) is a well-known tumor suppressor, and we intended to explore the role and mechanism of miR-130a in NSCLC cells under hypoxia. We used real-time quantitative polymerase chain reaction method to measure miR-130a expression, and found that miR-130a was downregulated in human NSCLC tumors and cell lines (A549 and H1299), accompanied with upregulation of hypoxia-inducible factor 1 alpha (HIF1A), a marker of hypoxia. Besides, miR-130a low expression was associated with tumor burden and poor overall survival. Moreover, miR-130a expression was even downregulated in hypoxia-treated A549 and H1299 cells. Ectopic expression of miR-130a suppressed Warburg effect, migration and invasion in hypoxic A549 and H1299 cells, as evidenced by decreased glucose consumption, lactate production, hexokinase 2 expression, and numbers of migration cells and invasion cells analyzed by commercial glucose and lactate assay kits, western blotting and transwell assays. EKI-785 manufacturer Furthermore, overexpression of miR-130a restrained xenograft tumor growth of A549 cells in mice. However, recovery of HIF1A could reverse the suppressive effect of miR-130a overexpression on cell migration, invasion and Warburg effect in hypoxic A549 and H1299 cells. Mechanically, dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down assay confirmed a target relationship between miR-130a and HIF1A. Collectively, we demonstrated an anti-tumor role of miR-130a in NSCLC cells under hypoxia through targeting HIF1A, suggesting a potential target for the interfering of NSCLC.Assessment of the effectiveness of school tobacco policies (STPs) in reducing adolescent smoking remains inconclusive. Previous studies took insufficient account of different dimensions of STPs, the different views of students and staff, and policy changes over time. This study assessed how a multidimensional STP, as perceived by students and staff, was associated with adolescent smoking over time in six European cities. The SILNE and SILNE-R surveys were conducted among students (n = 18,502) and staff (n = 438) in 38 schools in 2013 and 2016. Three dimensions (comprehensiveness, enforcement, and communication) were assessed and we calculated total STP scores. Multilevel logistic regressions estimated associations of STPs with adolescent smoking on and just outside school premises and with weekly smoking. Further analyses estimated associations between 2013 and 2016 STP changes and smoking outcomes in 2016, controlling for STP and smoking prevalence in 2013. On average, there were few increases in STP scores over time.
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